Dose-dense adjuvant chemotherapy in HER2-positive early breast cancer patients before and after the introduction of trastuzumab: Exploratory analysis of the GIM2 trial

Dose-dense adjuvant chemotherapy is standard of care in high-risk early breast cancer patients. However, its role in HER2-positive patients is still uncertain. In this exploratory analysis of the GIM2 trial, we investigated the efficacy of dose-dense chemotherapy in HER2-positive breast cancer patients with or without exposure to trastuzumab. In the GIM2 trial, node-positive early breast cancer patients were randomized to receive four cycles of (fluorouracil)epirubicin/cyclophosphamide followed by four cycles of paclitaxel administered every 2 (dose-dense) or 3 (standard-interval) weeks. After approval of adjuvant trastuzumab, protocol was amended in April 2006 to allow use of trastuzumab for 1 year after chemotherapy completion in HER2-positive patients. The efficacy of dose-dense chemotherapy in terms of disease-free survival (DFS) and overall survival (OS) was assessed according to HER2 status and trastuzumab use. Out of 2,003 breast cancer patients, HER2 status was negative/unknown in 1,551 patients; among the 452 patients with HER2-positive breast cancer, chemotherapy alone or followed by trastuzumab was given to 320 and 132 patients, respectively. Median follow-up was 8.1 years. No significant interaction between HER2 status, trastuzumab use and chemotherapy treatment was observed for both DFS (p = 0.698) and OS (p = 0.708). Nevertheless, there was no apparent benefit in the HER2-positive group treated with trastuzumab (DFS: HR, 0.99; 95% CI 0.52–1.89; OS: HR, 0.95; 95% CI 0.37–2.41). Although dose-dense chemotherapy was associated with a significant survival improvement in high-risk breast cancer patients, its benefit appeared to be smaller (if any) in patients with HER2-positive disease who received adjuvant trastuzumab.     

Hysteroscopic assessment of menopausal breast-cancer patients taking tamoxifen; there is a bias from the mode of endometrial sampling in estimating endometrial morbidity?

The aim of this study is to evaluate the accuracy of hysteroscopy in detecting tamoxifen-associated endometrial morbidity. Ninety-eight menopausal breast cancer patients taking tamoxifen underwent hysteroscopy because of an endometrial thickness above 4 mm measured by Transvaginal Ultrasonography. Thirty-one women recorded uterine bleeding while 67 were asymptomatic. Hysteroscopies with operative facilities were performed, mainly in out-patient setting. Hysteroscopic findings were matched with histopathology derived from various modalities of tissue collection as suction-curettage, oriented-streak curettage, hysteroscopically-targeted biopsies or polypectomies and hysterectomies. Accuracy of hysteroscopy to estimate a normal or abnormal endometrium was calculated. Abnormal endometrium was detected in 35 patients (64.5% in symptomatic and 22.3% in asymptomatic women, P < 0.001). We found six carcinomas, 18 polyps and 11 hyperplasias. Hysteroscopy showed sensitivity and specificity of 89.2 and 98.4%, respectively. By blind sampling, tissue collection was too scant to give a diagnosis in 29.1% of patients and in 80.5% of patients in whom hysteroscopy showed cystic atrophy the pathologist failed to confirm this condition. Moreover, eight endometrial polyps (36.3%) detected by hysteroscopy were missed. Conversely, by tissue sampling under vision no inadequate specimen was sent to the pathologist and all hysteroscopies showing cystic atrophy and polyps were pathologically confirmed. From literature data, the detection-rate of endometrial pathology in tamoxifen users varies from the lowest to the highest prevalences whether blind or hysteroscopically-targeted modalities of tissue sampling were used, respectively. Hysteroscopy with targeted sampling appears to be the most effective method to assess the endometrial lining. In our experience it is safe, well tolerated and it should be considered the reference test to assess a thickened endometrium in women under tamoxifen.     

Carboplatin plus taxol is an effective third-line regimen in recurrent undifferentiated nasopharyngeal carcinoma

BACKGROUND: Recurrent undifferentiated nasopharyngeal carcinoma is a chemosensitive disease. Few third-line treatments have been reported. METHODS: Twelve patients (9 males, 3 females; median age 50 years, range, 20-62) with recurrent undifferentiated nasopharyngeal carcinoma were treated with carboplatin AUC 5.5 + paclitaxel (175 mg/m2, 3-hr infusion) on day 1 every 3 weeks. All patients had been previously treated for recurrent disease with a first-line cisplatin-based chemotherapy and a second-line therapy with low-dose continuous infusion 5-fluorouracil. RESULTS: Overall, 54 courses were given (median, 5; range, 2-6). Three patients (25%) obtained a partial response lasting 6, 10 and 26+ months, 1 (8.3%) a minimal response lasting 6 months, and 3 (25%) no change with a median duration of 5 months. The median survival time was 14 months for patients who had a partial or minimal response or no change, and 5 months for nonresponders. Median overall survival was 9.5 months (3-30+). The treatment was well tolerated, and toxicity was manageable. CONCLUSIONS: The combination has a good palliative role as third-line chemotherapy in recurrent undifferentiated nasopharyngeal cancer.     

Periodontal disease: Is it a risk factor for premature labor, low birth weight or preeclampsia?]

OBJECTIVES: To determine if periodontal disease (PD) is a risk factor for premature labor, low birth weight, or preeclampsia, and to look for a potential association between the different clinical forms of PD and the obstetric results indicated. METHODS: This is an analytical, cross-sectional and prospective study of all women who gave birth in Dr. José Penna Hospital, in the city of Bahía Blanca, Argentina, between 1 February and 18 July 2003 and between 1 March and 31 May 2004. Women who met the inclusion criteria (being over 18 years old, having at least 18 teeth, not being diabetic, and having had children who survived labor) underwent a dental exam to look for hemorrhage when teeth were probed, loose teeth, or inflammation of the gums, and any loss of insertion was measured clinically. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated, and the results were adjusted according to smoking status and the presence or absence of anemia. RESULTS: A total of 2,003 births and 1,982 labor episodes were registered. In all, 420 women (21.2%) were excluded from the study because they did not meet the inclusion criteria or because no diagnostic exam could be carried out. Of the 1,562 women who were examined, 809 (51.8%) had at least one of the problems being sought; of these women, 274 (17.5%) had severe periodontal disease, and 535 (34.3%) had gingivitis. In all, there were 149 (9.5%) cases of premature labor; 161 (10.3%) cases of low birth weight, and 157 (10.0%) cases of preeclampsia. No association was noted between PD and premature labor (OR = 1.06; 95% CI: 0.74 to 1.50), low birth weight (OR = 1.05; 95% CI: 0.74 to 1.47), or preeclampsia (OR = 0.99; 95% CI: 0.70 to 1.40). The risk of giving birth to an infant with low birth weight in the subgroup of women who smoked more than 10 cigarettes a day was greater among women who had severe PD than among those who had good oral health (OR = 3.81; 95% CI: 1.46 to 10.05; P = 0.001). Anemia was found to be a risk factor for low birth weight (OR = 1.74; IC 95%: 1.03 to 2.94; P = 0.02). CONCLUSIONS: No significant association was found between PD and premature labor, low birth weight, or preeclampsia.     

A phase II study on metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history of HER2-positive disease

Purpose: To observe whether in pretreated metastatic breastcancer patients with HER2-positive disease vinorelbine plustrastuzumab can produce different overall response rate (ORR),time to progression (TTP), and overall survival (OS) from womenwith HER2-negative tumors treated with vinorelbine alone. Methods: Between June 2000 and January 2004, 68 consecutivewomen were enrolled: 33 patients received vinorelbine (V) alone,while 35 patients were given trastuzumab plus vinorelbine (T+V)according to HER2 expression determined by immunohistochemistry.In tumors scored +2, HER2 gene amplification was determinedby fluorescence in situ hybridization. Results: In patients treated with V (HER2-negative tumors) theORR was 27.3%, while in those given T+V (HER2 positive tumors)the ORR was 51.4%. The median duration of response was 8 monthsfor women treated with V and 10 months for those who receivedT+V. Patients given T+V had a longer TTP (9 months) and OS (27months) than those receiving V alone (6 months and 22 monthsrespectively). Toxicity was mild in both groups. Concerningcardiotoxicity in T+V group, 7 patients (20%) had left ventricularsystolic disfunction. Conclusion: Our data suggest that trastuzumab can change thenatural history of HER2-positive metastatic breast cancer. Infact, when treated with trastuzumab, women with HER2-positivedisease had better prognosis than patients with HER2-negativetumors. Conducting a formal phase III trial comparing vinorelbinealone vs vinorelbine plus trastuzumab in HER2-positive metastaticbreast cancer women could be debatable. Key words: weekly vinorelbine, trastuzumab, HER2, metastatic breast cancer     

Mandibular fractures in sports. Retrospective study of 48 cases

We present a retrospective study of 48 isolated mandibular fractures related to athletic activities. We studied patient age, sex, sport involved, mandibular location of the fracture and the therapeutic implication. The sex ratio was 4/1 and mean age 24 years. Rugby and cross-country biking were the more frequently involved sports (79%). We recall preventive measures. Miniplate osteosynthesis was used as often as possible in order to avoid intermaxillary fixation (IMF) (40%) or to limit the duration of IMF. This allowed early return to sport activities.     

Bovine seminal ribonuclease is cytotoxic for both malignant and normal telomerase-positive cells

Bovine seminal-ribonuclease (BS-RNase) is a member of the 'ribonucleases with special biological actions' family since it possesses specific anti-tumour, anti-spermatogenic and embryotoxic activities and exerts an immunosuppressive effect on T lymphocytes. In previous studies it was demonstrated that BS-RNase induced apoptosis in proliferating, malignant and normal cells and that telomerase activity loss also caused apoptotic death in neoplastic cells. Since an obvious relationship between cell proliferation and telomerase activity exists, the aim of this work was to study if the pro-apoptotic cytotoxic action exerted by BS-RNase on proliferating malignant cells (HT29) and proliferating normal cells (PHA-stimulated lymphocytes) could be linked to a possible BS-RNase effect on telomerase activity. In BS-RNase-treated HT29 cells (Na-butyrate-differentiated or not) and human lymphocytes (proliferating or not), we investigated cell vitality (MTT method) and morphology (SEM), BS-RNase localization (immunofluorescence), telomerase activity (TRAP-ELISA method), hTR mRNA expression (RT-PCR), and hTERT levels (western blot). While no BS-RNase effect was detectable on not proliferating cells, a clear relationship was noticed between the diminished number of vital elements of both proliferating cell populations after treatment (48 h and 72 h for HT29 and PHA-stimulated lymphocytes, respectively) with 50 microg/ml BS-RNase and the decrease of their telomerase activity. At the same time, we found that hTR levels, the RNA subunit of telomerase, in proliferation-inhibited BS-RNase-treated cells were diminished. Moreover, by immunofluorescence technique, we detected BS-RNase in the HT29 cell nucleolus after 3-h treatment. Therefore, as hTR has been recently proven to co-fractionate with nucleoli, we hypothesize that a BS-RNase direct action on the telomerase hTR subunit could be a possible mechanism of action by which BS-RNase exerts its pro-apoptotic effects only on proliferating cells.